This proposal aims to advance the current understanding of the cellular and molecular immune events that associate with the increased susceptibility to develop systemic lupus erythematosus (SLE) in females. Gender disparities associate with several biological differences that most apparently involve an evident dissimilarity between sexes in the levels of sex hormones and their receptors. However, although very important, the differences in the expression and responsiveness to sex hormones may not be sufficient to fully explain the increased incidence of SLE in females. During the past decade, our group has been interested in investigating the effects of the hormone adipokine leptin on immune responses. We and others have shown that this sexually dimorphic hormone - found at concentrations 5-10 times higher in females than in males with similar body mass index - has proinflammatory activities that greatly favor the development and the progression of several autoimmune diseases including SLE. We have also shown that leptin constraints the ability of regulatory T cells to suppress autoreactive immune responses in vitro and in vivo, and together with others we have shown that regulatory T cells can modulate SLE disease activity. Here we propose to dissect the effects of leptin on regulatory T cells in SLE by testing the hypothesis that elevated levels of leptin in females can modulate key characteristics of the regulatory T cells in SLE. Three integrated aims will study the influence of leptin on the phenotype and function of regulatory T cells in SLE at the cellular, molecular and biochemical levels. By identifying specific events that can be modulated by leptin in SLE, we aim to ultimately identify surrogate markers of therapeutic intervention that could lead to a better management of the disease. PUBLIC HEALTH RELEVANCE: In this application we will explore new mechanisms that may contribute to the increased susceptibility to develop systemic lupus erythematosus ( SLE) in females. We will investigate the role of a hormone that is expressed in much higher concentration in females as a possible major contributor to the pathogenesis of SLE. The role of this hormone, leptin, will be investigated in great detail for its capacity to inhibit the activity of cells that suppress autoimmunity in SLE, as preliminary work seems to suggest.